The neuroectodermal tumors neuroblastoma and melanoma represent biologically aggressive and chemoresistant cancers. The chemotherapeutic agents fenretinide and bortezomib induce apoptosis through ...endoplasmic reticulum (ER) stress in these tumor types. The aim of this study was to test the hypothesis that the early events of ER stress signaling and response pathways induced by fenretinide and bortezomib are mediated by the eukaryotic initiation factor 2α (eIF2α)-ATF4 signaling pathway. Treatment of neuroblastoma and melanoma cell lines with fenretinide, bortezomib, or thapsigargin resulted in induction of eIF2α signaling, characterized by increased expression of phosphorylated eIF2α, ATF4, ATF3, and GADD34. These events correlated with induction of the pro-apoptotic protein Noxa. The cytotoxic response, characterized by up-regulation of Noxa and cell death, was dependent on ATF4, but not the ER-related pro-death signaling pathways involving GADD153 or IRE1. Although PERK-dependent phosphorylation of eIF2α enhanced ATF4 protein levels during ER stress, cell death in response to fenretinide, bortezomib, or thapsigargin was not abrogated by inhibition of eIF2α phosphorylation through PERK knockdown or overexpression of wild-type eIF2α. Furthermore, ATF4 induction in response to ER stress was dependent primarily on transcriptional activation, which occurred in a PERK- and phosphorylated eIF2α-independent manner. These results demonstrate that ATF4 mediates ER stress-induced cell death of neuroectodermal tumor cells in response to fenretinide or bortezomib. Understanding the complex regulation of cell death pathways in response to ER stress-inducing drugs has the potential to reveal novel therapeutic targets, thus allowing the development of improved treatment strategies to overcome chemoresistance.
This was a first-in-human Phase 1/2 open-label dose-escalation study of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737.
Patients with advanced solid tumours enrolled in dose-escalation cohorts ...and received SRA737 monotherapy orally on a continuous daily (QD) dosing schedule in 28-day cycles. Expansion cohorts included up to 20 patients with prospectively selected, pre-specified response predictive biomarkers.
In total, 107 patients were treated at dose levels from 20-1300 mg. The maximum tolerated dose (MTD) of SRA737 was 1000 mg QD, the recommended Phase 2 dose (RP2D) was 800 mg QD. Common toxicities of diarrhoea, nausea and vomiting were generally mild to moderate. Dose-limiting toxicity at daily doses of 1000 and 1300 mg QD SRA737 included gastrointestinal events, neutropenia and thrombocytopenia. Pharmacokinetic analysis at the 800 mg QD dose showed a mean C
of 312 ng/mL (546 nM), exceeding levels required to cause growth delay in xenograft models. No partial or complete responses were seen.
SRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy.
Clinicaltrials.gov NCT02797964.
Inhibition of monocarboxylate transporter (MCT) 1-mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a ...first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer.
This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics.
During dose escalation, 40 patients received AZD3965 at 5-30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity.
AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).
5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging ...administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU.
NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity.
Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0-11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival.
NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m
NUC-3373 weekly. NUC-3373 is currently in combination treatment studies.
Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240 .
Infants and young children represent an important but much understudied childhood cancer patient population. The pharmacokinetics and pharmacogenetics of the widely used anticancer prodrug ...cyclophosphamide were investigated in children <2 years of age. Concentrations of cyclophosphamide and selected metabolites were determined in patients administered cyclophosphamide at doses ranging from 100-1500 mg/m
(5-75 mg/kg), with various infusion times as determined by the standard treatment regimen that each patient was receiving. Polymorphisms in genes including CYP2B6 and CYP2C19 were investigated. Data generated for cyclophosphamide were analysed using a previously published population pharmacokinetic model. Cyclophosphamide pharmacokinetics was assessed in 111 samples obtained from 25 patients ranging from 4-23 months of age. The average cyclophosphamide clearance for the patients was 46.6 mL/min/m
(ranging from 9.4-153 mL/min/m
), with marked inter-patient variability observed (CV 41%). No significant differences in cyclophosphamide clearance or exposure (AUC) were observed between patient groups as separated by age or body weight. However, marked differences in drug clearance and metabolism were noted between the current data in children <2 years of age and recently published results from a comparable study conducted by our group in older children, which reported significantly lower cyclophosphamide clearance values and metabolite exposures using the same population pharmacokinetic model for analysis. Whilst this study demonstrates no significant differences in cyclophosphamide clearance in patients <2 years, it highlights large differences in dosing protocols across tumour types. Furthermore, the study suggests marked differences in cyclophosphamide clearance in children less than two years of age as compared to older patients.
Cancer in neonates and infants is a rare but challenging entity. Treatment is complicated by marked physiological changes during the first year of life, excess rates of toxicity, mortality, and late ...effects. Dose optimisation of chemotherapeutics may be an important step to improving outcomes. Body size–based dosing is used for most anticancer drugs used in infants. However, dose regimens are generally not evidence based, and dosing strategies are frequently inconsistent between tumour types and treatment protocols. In this review, we collate available pharmacological evidence supporting dosing regimens in infants for a wide range of cytotoxic drugs. A systematic review was conducted, and available data ranked by a level of evidence (1–5) and a grade of recommendation (A–D) provided on a consensus basis, with recommended dosing approaches indicated as appropriate. For 9 of 29 drugs (busulfan, carboplatin, cyclophosphamide, daunorubicin, etoposide, fludarabine, isotretinoin, melphalan and vincristine), grade A was scored, indicating sufficient pharmacological evidence to recommend a dosing algorithm for infants. For busulfan and carboplatin, sufficient data were available to recommend therapeutic drug monitoring in infants. For eight drugs (actinomycin D, blinatumomab, dinutuximab, doxorubicin, mercaptopurine, pegaspargase, thioguanine and topotecan), some pharmacological evidence was available to guide dosing (graded as B). For the remaining drugs, including commonly used agents such as cisplatin, cytarabine, ifosfamide, and methotrexate, pharmacological evidence for dosing in infants was limited or non-existent: grades C and D were scored for 10 and 2 drugs, respectively. The review provides clinically relevant evidence-based dosing guidance for cytotoxic drugs in neonates and infants.
•Treating cancer in neonates and infants is challenging.•Dose optimisation of cytotoxic drugs is an important step to improving outcomes.•Clinical pharmacological evidence supporting dosing regimens in infants was collated.•All available pharmacological evidence was ranked by a level of evidence.•A grade of recommendation was derived and a recommended dose per agent provided.
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